This invention relates to compounds that inhibit farnesyl protein transferase and ras protein farnesylation, thereby making them useful as anticancer agents. The compounds are also useful in the treatment of diseases, other than cancer, associated with signal transduction pathways operating through ras and those associated with CAAX-containing proteins other than ras that are also post-translationally modified by the enzyme farnesyl protein transferase. The compounds may also act as inhibitors of other prenyl transferases, and thus be effective in the treatment of diseases associated with other prenyl modifications of proteins.
The mammalian ras gene family comprises three genes, H-ras, K-ras and N-ras. The ras proteins are a family of GTP-binding and hydrolyzing proteins that regulate cell growth and differentiation. Overproduction of normal ras proteins or mutations that inhibit their GTPase activity can lead to uncontrolled cell division. The transforming activity of ras is dependent on localization of the protein to plasma membranes. This membrane binding occurs via a series of posttranslational modifications of the cytosolic ras proteins. The first and mandatory step in this sequence of events is the farnesylation of these proteins. The reaction is catalyzed by the enzyme farnesyl protein transferase (FPT), and farnesyl pyrophosphate (FPP) serves as the farnesyl group donor in this reaction. The ras C-terminus contains a sequence motif termed a xe2x80x9cCys-Aaa1-Aaa2-Xaaxe2x80x9d box (CAAX box), wherein Cys is cysteine, Aaa is an aliphatic amino acid, and Xaa is a serine or methionine. Farnesylation occurs on the cysteinyl residue of the CAAX box (Cys-186), thereby attaching the prenyl group on the protein via a thio-ether linkage.
In accordance with the present invention, compounds of the formulas I and II 
their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof inhibit farnesyl protein transferase which is an enzyme involved in ras oncogene expression. In formulas I-II and throughout their specification, the above symbols are defined as follows:
r, s and t are 0 or 1;
m=0, 1, 2;
p is 0, 1 or 2;
X1 and X2 are, independently, selected from the group consisting of oxygen, hydrogen, R1, R2, or R3;
Y is selected from the group consisting of CHR9, SO2, CO, CO2, O, NR10, SO2NR11 AND CONR12; R6, R7, R9, R10, R11, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27 and R28 are selected from the group consisting of hydrogen, lower alkyl or substituted alkyl;
R4, R5 are selected from the group consisting of hydrogen, halo, nitro, cyano and U-R13; R4 and R5 may join together to form a carbocyclic or heterocyclic ring;
R12 is selected from the group consisting of hydrogen, lower alkyl, aryl, substituted alkyl or aryl;
U is selected from the group consisting of sulfur, oxygen, NR14, CO, SO, SO2, CO2, NR15CO2, NR16CONR17, NR18SO2NR19SO2NR20, SO2NR21, NR22CO, CONR23, PO2R24 and PO2R25 or U is absent;
R1, R2, R3, R8 and R13 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo;
R, S and T are selected from the group consisting of CH2, CO and CH(CH2)pQ wherein Q is NR26R27 or OR28;
and A, B, C and D are carbon, oxygen, sulfur or nitrogen, with the proviso that R13 may be hydrogen except when U is SO, SO2, NR15CO2 or NR18SO2.
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The expression xe2x80x9clower alkylxe2x80x9d refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. SO2NH2, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. CONH2, substituted carbamyl e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituent is further substituted it will be with alkyl, alkoxy, aryl or aralkyl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to fluorine, chlorine, bromine and iodine.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
The term xe2x80x9caralkylxe2x80x9d refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to an aryl group substituted by, for example, one to four substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, aralkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituent may be further substituted by hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
The term xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four double bonds.
The term xe2x80x9csubstituted alkenylxe2x80x9d refers to an alkenyl group substituted by, for example, one to two substituents, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
The term xe2x80x9calkynylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four triple bonds.
The term xe2x80x9csubstituted alkynylxe2x80x9d refers to an alkynyl group substituted by, for example, a substituent, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring.
Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The terms xe2x80x9cheterocyclexe2x80x9d, heterocyclic and xe2x80x9cheterocyclexe2x80x9d refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl, and the like.
Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl) or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and the like.
Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents. Also included are smaller heterocycles, such as, epoxides and aziridines.
The term xe2x80x9cheteroatomsxe2x80x9d shall include oxygen, sulfur and nitrogen.
The xe2x80x98ABCDxe2x80x99 fused ring to the diazepine ring may be monocyclic or bicyclic, e.g. naphthyl or quinolyl in nature.
The compounds of formulas I-II may form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g, in isolating or purifying the compounds of this invention.
The compounds of formulas I-II may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts may be obtained, for example, by exchanging the carboxylic acid protons, if they contain a carboxylic acid, in compounds I-II with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by evaporation. Other salts can be formed as known to those skilled in the art.
The compounds for formulas I-II may form salts with a variety of organic and inorganic acids. Such salts include those formed with hydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts may be formed by reacting compounds I-II in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by evaporation. In addition, zwitterions (xe2x80x9cinner saltsxe2x80x9d) may be formed.
Compounds of the formulas I-II may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formulas I-II) is a prodrug within the scope and spirit of the invention.
For example compounds of the formulas I-II may be a carboxylate ester moiety. The carboxylate ester may be conveniently formed by esterifying any of the carboxylic acid functionalities found on the disclosed ring structure(s).
Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by KrosgaardLarsen and H. Bundgaard, Chapter 5, xe2x80x9cDesign and Application of Prodrugs,xe2x80x9d by H. Bundgaard, p. 113-191 (1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and
e) N. Kakeya, et al., Chem Phar Bull, 32, 692 (1984).
It should further be understood that solvates (e.g., hydrates) of the compounds of formulas I-II are also with the scope of the present invention. Methods of solvation are generally known in the art.
Preferred Moieties
For compounds of the present invention, the following moieties are preferred:
Compounds of formulas I and II wherein xe2x80x9cABCDxe2x80x9d and xe2x80x9cABCxe2x80x9d are a carbocyclic ring.
More preferred are compounds of formula I wherein m is one and xe2x80x9cABCDxe2x80x9d is a carbocyclic ring, e.g. benzo.
Use and Utility
The compounds of formulas I-II are inhibitors of S-farnesyl protein transferase. They are thus useful in the treatment of a variety of cancers, including (but not limited to) the following;
carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, ovary, prostate, testes, pancreas, esophagus, stomach, gall bladder, cervix, thyroid and skin, including squamous cell carcinoma;
hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, and Burketts lymphoma;
hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia;
tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas;
tumors of mesenchymal origin, including fibrosarcoma, rhabdomyoscarcoma, and osteosarcoma;
other tumors, including melanoma, xenoderma pigmentosum, keratoactanthoma, seminoma, thyroid follicular cancer and teratocarcinoma.
The compounds of formulas I-II are especially useful in treatment of tumors having a high incidence of ras involvement, such as colon, lung, and pancreatic tumors and in tumors in which a prenyl transferase contributes to tumor maintenance, tumor growth or tumor development. By the administration of a composition having one (or a combination) of the compounds of this invention, development of tumors in a mammalian host is reduced, or tumor burden is reduced, or tumor regression is produced.
Compounds of formulas I-II may also inhibit tumor angiogenesis, thereby affecting the growth of tumors. Such anti-angiogenesis properties of the compounds of formulas I-II may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
Compounds of formulas I-II may also be useful in the treatment of diseases other than cancer that may be associated with signal transduction pathways operating through ras, e.g., neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, polycystic kidney disease and endotoxic shock. Compounds I-II may be useful as anti-fungal agents.
Compounds of formula I-II may induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases. Compounds of formula I-II, as modulators of apoptosis, will be useful in the treatment of a variety of human diseases with aberrations in apoptosis including cancer (particularly, but not limited to follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostrate and ovary, and precancerous lesions such as familial adenomatous polyposis), viral infections (including but not limited to herpes virus, pox virus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases (including but not limited to systemic lupus erythematosus, immune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowl diseases and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer""s disease, AIDS-related dementia, Parkinson""s disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), AIDS, myelodysplastic syndromes, aplastic anemia, ischemic injury associated myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol induced liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases, and cancer pain.
Compounds of formulas I-II may also be useful in the treatment of diseases associated with farnesyl transferase substrates other than ras (e.g., nuclear lamins, transducin, rhodopsin kinase, cGMP phosphodiesterase, TC21, phosphorylase kinase, Rap2, RhoB, RhoE, PRL1) that are also post-translationally modified by the enzyme farnesyl protein transferase.
Compounds of formulas I-II may also act as inhibitors of other prenyl transferases (e.g., geranylgeranyl transferase I and II), and thus be effective in the treatment of diseases associated with to other prenyl modifications (e.g., geranylgeranylation) of proteins (e.g. the rap, rab, rac and rho gene products and the like). For example, they may find use as drugs against Hepatitis delta virus (HDV) infections, as suggested by the recent finding that geranylgeranylation of the large isoform of the delta antigen of HDV is a requirement for productive viral infection [J. S. Glen, et al., Science, 256, 1331 (1992)].
The compounds of this invention may also be useful in combination with known anti-cancer and cytotoxic agents and treatments, including radiation. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. Compounds of formulas I-II may be used sequentially with known anticancer or cytotoxic agents and treatment, including radiation when a combination formulation is inappropriate. Suitable cytotoxic agents which may be used in combination with the compounds of the present invention include the taxanes, e.g. paclitaxel, docetaxel or derivatives thereof; camptothecin derivatives e.g. topotecon or CPT-11; gemcitabine; platinum compounds e.g. cisplatin or carboplatin; telomerase inhibitors; various alkylating agents and tubulin stabilizing agents, e.g. epothilones among others.
Farnesyl transferase assays were performed as described in V. Manne et al., Drug Development Research, 34, 121-137, (1995). The compounds of Examples 1-50 inhibited farnesyl transferase with IC50 values between 0.1 nM and 100 xcexcM.
The compounds of this invention may be formulated with a pharmaceutical vehicle or diluent for oral, intravenous, intraperitoneal, subcutaneous, intraabdominal, intramuscular, rectal, vaginal or topical administration. Oral administration may involve the use of slow release formulations, such as biodegradable polymers or prodrugs. The pharmaceutical composition can be formulated in a classical manner using solid or liquid vehicles, diluents and additives appropriate to the desired mode of administration. Orally, the compounds can be administered in the form of tablets, capsules, granules, powders and the like. The compounds may be administered in a dosage range of about 0.05 to 200 mg/kg/day, preferably less than 400 mg/kg/day, in a single dose or in 2 to 4 divided doses. 
wherein R1 is selected from arylalkyl, aryl, substituted aryl, heteroaryl; R2 is selected from hydrogen, bromine, CN, alkyl or aryl; R3 is selected from H, alkyl, subtituted alkyl, arylalkyl.
Step 1
A mono-protected ethylenediamine derivative is reductively alkylated with an aldehyde and a reducing agent such as NaCNBH3 or Na(OAc)3BH in an alcoholic solvent such as methanol in the presence of an acid such as acetic acid at from 0xc2x0 C. to room temperature.
Step 2
The resulting mono-protected ethylenediamine derivative is sulfonylated with a 2-halo-arylsulfonyl chloride in a mixed aqueous/organic solvent system such as aqueous NaOH/methylene chloride at from 0xc2x0 C. to room temperature.
Step 3
The amine protecting group is removed (e.g., Boc by an acid such as TFA in an organic solvent such as methylene chloride).
Step 4
The resulting compound is cyclized by heating in an organic solvent such as DMF in the presence of a base such as K2CO3 at from 50xc2x0 C. to 100xc2x0 C.
Step 5
The resulting compound is reductively alkylated with an imidazole containing aldehyde and a reducing agent such as NaCNBH3 or Na(OAc)3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at from 0xc2x0 C. to room temperature. 
wherein R1 is selected from substituted alkyl, arylalkyl, aryl, substituted aryl, heteroaryl and R2 is selected from hydrogen, amino, substituted amino, halo, cyano, alkyl, substituted alkyl, aryl, heteroaryl or the combination of these groups.
Step 1
A 2-haloethylamine is sulfonylated with a 2-nitro-arylsulfonyl chloride in a mixed aqueous/organic solvent system such as aqueous NaHCO3/methylene chloride at from 0xc2x0 C. to room temperature.
Step 2
The nitro group of the resulting compound is reduced to an amine, e.g., with SnCl2 in an organic solvent such as ethyl acetate at room temperature.
Step 3
(a) The resulting aniline derivative is cyclized by heating in an alcoholic solvent such as ethanol.
(b) The compound where R2 is bromo can be prepared by treatment of the compound where R2 is H with bromine in a mixed organic solvent system such as DMF/acetic acid at room temperature.
Step 4
(a) The resulting compound is alkylated by R1-L (where L is a leaving group such as a halide or a sulfonate) in an organic solvent system such as DMF in the presence of a base such as K2CO3 and a catalyst such as 18-crown-6 at from room temperature to 60xc2x0 C.
(b) Where R1 is aryl or heteroaryl, the reaction is performed in a suitable solvent such as collidine in the presence of a copper compound such as copper oxide at from 100xc2x0 C. to 170xc2x0 C.
(c) The compound where R1 is oxadiazolylaryl is prepared from the compound where R1 is alkoxycarbonylaryl by reaction with a N-hydroxyamidine derivative in a suitable solvent such as DMF in the presence of a base such as NaH at from 0xc2x0 C. to 100xc2x0 C.
(d) The compound where R2 is bromo is prepared by treatment of the compound with a brominating reagent such as bromine in a mixed organic solvent system such as DMF/acetic acid, or tetrabutylammonium tribromide in chloroform at from 0xc2x0 C. to room temperature. The compound where R2 is aryl is prepared by reaction of the bromo derivative with an aryl metal derivative such as phenylboronic acid in, for example, a deoxygenated mixed aqueous/organic solvent system such as aqueous NaHCO3/toluene in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)-palladium at from room temperature to 100xc2x0 C. This arylation reaction may also be performed in Step 3 of Scheme 2.
(e) The compound where R2 is cyano group is prepared by treatment of the compound where R2 is bromide with a metal cyanide such as copper cyanide in a suitable solvent such as NMP at an elevated temperature such as 180xc2x0 C.
(f) The compound where R2 is R4CONHCH2 is prepared from the compound where R2 is CN by reduction with, for example, lithium aluminum hydride followed by acylation under standard conditions. The resulting compound is reductively alkylated as described in Step 5 of Scheme 1 to give a desired compound of formula I. 
wherein R1 is selected from substituted alkyl, arylalkyl, aryl, substituted aryl, heteroaryl; R2 is selected from hydrogen, amino, substituted amino, halo, cyano, alkyl, substituted alkyl, aryl, heteroaryl or the combination of these groups; R3 is selected from H, alkyl, subtituted alkyl, arylalkyl.
Step 1
An example is protected on the imidazole nitrogen, e.g., with trityl by treatment with triphenylmethylchlorde in an organic solvent such as pyridine at from 0xc2x0 C. to room temperature.
Step 2
The resulting compound is alkylated with R3L (where L is a leaving group such as a halide or a sulfonate) in an organic solvent system such as DMF in the presence of a base such as diisopropylethylamine. Deprotection, e.g., with TFA and triethylsilane at from 0xc2x0 C. to room temperature affords a target compound of formula I. 
wherein R1 is selected from H, substituted alkyl, arylalkyl, aryl, heteroaryl; R2 and R4 are selected from H, halo, NO2, NH2, CN, alkyl, substituted alkyl, arylalkyl, alkoxy and substituted amino and R2 and R4 may together form a carbocyclic or heterocyclic ring; R3 is selected from H, substituted alkyl, arylalkyl.
Step 1
An amino acid ester with an optional nitrogen substitutent is sulfonylated with a 2-nitro-arylsulfonyl chloride in a mixed aqueous/organic solvent system such as aqueous NaHCO3/methylene chloride at from 0xc2x0 C. to room temperature. Alternatively, an amine is sulfonylated with a 2-nitro-benzenesulfonyl chloride, followed by alkylation of the resultant sulfonamide with a haloalkylester such as ethyl bromoacetate.
Step 2
(a) The nitro group of the resulting compound is reduced to an amine as in Step 2 of Scheme 2. If R2 is a nitro group, that group is also reduced to an amine.
(b) If R1 is H, the sulfonamide nitrogen can be alkylated at this step as described in Step 4 of Scheme 2.
Step 3
The carboxylic ester is converted to the carboxylic acid with a base such as lithium hydroxide in a mixed aqueous organic solvent such as THF-H2O-MeOH at room temperature.
Step 4
(a) The resultant carboxylic acid is cyclized with a dehydrating agent such as Bop chloride in an organic solvent such as DMF in the presence of a base such as diisopropylethylamine at from 0xc2x0 C. to room temperature.
(b) If R2 is an amine, it may be reductively alkylated with an aldehyde such as formadehyde in the presence of a reducing agent such as sodium cyanoborohydride. In addition, the amine group may be converted to a bromide by treatment with a nitrosating agent such as tert-butyl nitrite, followed by a metal bromide such as copper (II) bromide. This bromination reaction may also be done after the amide is reduced (Step 5a of Scheme 4). Multiple bromination can occur in this process.
Step 5
(a) The amide is reduced with a reducing agent such as borane in an organic solvent such as THF at from 0xc2x0 C. to reflux.
(b) If R1 is H, the sulfonamide nitrogen may be substituted as described in Step 4 of Scheme 2.
(c) If R1 is H and R2 is H, the sulfonamide nitrogen may be sulfonylated with an alkyl or aryl sulfonyl chloride such as methanesulfonyl chloride in the presence of a base such as n-butyl lithium.
(d) If R2 is H, the sulfonamide may be brominated by following the Step 4 (d) of Scheme 2.
(e) If R2 is an amine, it may be acylated with an acid chloride in an organic solvent such as methylene chloride in the presence of a base such as pyridine at from 0xc2x0 C. to room temperature. In addition, it may be brominated by following the Step 4 (d) of Scheme 2. The product is then reductively alkylated as described for Step 5 of Scheme 1 to give the final desired compound. 
wherein R1 and R2 are selected from H, substituted alkyl, arylalkyl, aryl, heteroaryl; R3 is selected from H, substituted alkyl, arylalkyl; R4, R5 are selected from H, halo, CN, alkyl, arylalkyl, aryl, heteroaryl or R4 and R5 may together to form a carbocyclic or heterocyclic ring.
Step 1
An aniline derivative is acylated with an anhydride such as trifluoroacetic anhydride in an organic solvent such as methylene chloride in the presence of a base such as pyridine at from 0xc2x0 C. to room temperature.
Step 2
The amide is treated with a sulfonylating agent such as chlorosulfonic acid in an organic solvent such as chloroform at from about 0xc2x0 C. to room temperature.
Step 3
The sulfonyl chloride is reacted with an optionally substituted aminoalcohol as described in Step 2 of Scheme 1.
Step 4
The resultant sulfonamide is cyclized by treatment with a dehydrating agent like DEAD/triphenylphosphine in an organic solvent such as THF.
Step 5
The amide is hydrolyzed by, for example, treatment with a base such as potassium carbonate in an organic solvent such as methanol. The product is then reductively alkylated as described for Step 5 of Scheme 1 to give the desired compound of formula I.
The invention will now be further described by the following working examples, which are preferred embodiments of the invention. All temperatures are in degrees Celsius (xc2x0 C.) unless otherwise indicated. These examples are illustrative rather than limiting.